Severe sepsis results in significant morbidity and mortality. Treatment options are limited and potentially unsuccessful. Mechanistic information on this disease process is essential if more efficacious treatments are to be found. Apoptosis of multiple cells types contributes to the high morbidity with severe sepsis. In sepsis, bacterial clearance is primarily achieved by Kupffer cells, the resident macrophages of the liver. Kupffer cells undergo apoptosis during severe sepsis, and this is associated with organ dysfunction and mortality. Other organs impact the degree of bacteremia as well. Gastrointestinal (GI) epithelial cells undergo apoptosis during sepsis allowing enteric bacteria to translocate across the GI epithelium and enter the systemic circulation. Cardiac myocyte apoptosis during severe sepsis could contribute to impaired blood flow and perpetuate dysfunction of other organs. Lastly, apoptosis of vascular endothelial cells contributes to microvascular dysfunction in sepsis, which may lead to impaired tissue perfusion. Mitochondrial antioxidants are known to prevent cellular apoptosis in response to oxidative stress such as that associated with sepsis. Superoxide dismutase 2 (SOD2) is the most abundant mitochondrial antioxidant. Two pathways have emerged which may directly influence mitochondrial antioxidant function. These pathways involve signaling via insulin-like growth factor 1 (IGF-1) and angiotensin II (AngII). It is of note that IGF-1 levels are decreased in severe sepsis, while AngII is upregulated. AngII is a potent vasoconstrictor that is an important determinant of oxidant stress and cellular apoptosis. Lack of circulating IGF-1 impairs cell survival and function. The hypothesis of this proposal is that pathologic interactions between angiotensin II and IGF-1 influence SOD2 levels in specific organs and contribute to impaired hepatic bacterial clearance and poor outcome in severe sepsis. In Aim 1, we will use our defined acute sepsis model to study the organ-specific role of SOD2. We will generate tissue-specific SOD2 knock-out mice to determine how impaired SOD2 contributes to bacterial clearance and survival in sepsis. In Aim 2, we will use the same model (and mice generated in Aim 1) to study the role of IGF-1 and angiotensin II in organ-specific SOD2 activity during sepsis. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal are essential to the field of sepsis research and have a high likelihood of translating into studies involving human subjects. These experiments will decipher, for the first time, each individual organ system's effect on bacterial clearance and outcome in sepsis. These studies have the potential to greatly impact the management of a complex disease which has a high mortality and, thus far, few therapeutic options which improve outcome.